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David R Vera

Publications and source records attributed to David R Vera.

At least 19 recordsLinked to original sources

Comparison of lesion-to-cerebellum uptake ratios and standardized uptake values in the evaluation of lung nodules with 18F-FDG PET.

OBJECTIVE: To evaluate the clinical performance of the lesion-to-cerebellum uptake ratio (LCR), a semiquantitative index for differentiating malignant from benign lung nodules with [F]fluorodeoxyglucose positron emission tomography (F-FDG PET). METHODS: Thirty-six patients (16 females, 20 males; median age, 73 years; range, 41-87 years) with 42 known or suspected malignant lung nodules underwent whole-body PET imaging after an intravenous injection of a mean dose of 543+/-69 MBq (14.7+/-1.9 mCi) of F-FDG. The standardized uptake value (SUV) and the LCR were calculated for each nodule and receiver operating characteristic (ROC) curves were analysed using the ROCKIT 0.9B software package. RESULTS: Surgical pathology and follow-up with serial computed tomography scans for at least 24 months revealed 18 malignant lung lesions and 24 benign lesions less than 3.0 cm in size. The mean LCR was 0.70+/-0.40 for malignant nodules and 0.23+/-0.12 for benign nodules (P<0.001, two-tailed test). The area under the estimated ROC curve was 0.8660 for SUV data and 0.9197 for LCR data (P=0.2408, two-tailed test). CONCLUSIONS: The LCR method appears to be a valuable semiquantitative index for the evaluation of malignancy in pulmonary nodules with F-FDG PET, which is simple to perform clinically and does not require accurate measurements of body weight or the residual activity in the syringe utilized for F-FDG injection.

Adult↗

Lymphoseek: a molecular imaging agent for melanoma sentinel lymph node mapping.

BACKGROUND: Lymphoseek is a molecular imaging agent specifically designed for sentinel lymph node mapping. We conducted a phase I clinical trial in which Lymphoseek was compared with filtered [(99m)Tc]sulfur colloid (fTcSC) for melanoma sentinel lymph node detection. METHODS: Twenty-four patients (33-81 years) with melanoma participated in this study. Four groups of six patients received an intradermal administration (.5 mCi) of 1.0, 5.0, or 10.0 nmol of (99m)Tc-labeled Lymphoseek or filtered [(99m)Tc]sulfur colloid. The injection site clearance was monitored by nuclear imaging for 3 hours. Lymph nodes obtained by gamma-guided biopsy (4.0-8.7 hours after injection) were assayed for radioactivity. Clinical chemistry values were monitored (before injection, before surgery, and 4 and 24 hours), and whole-body scans were acquired at 1 and 12 hours after injection. RESULTS: Lymphoseek exhibited a significantly (P < .001) faster injection site clearance at all dose levels. The mean Lymphoseek clearance half-time was 2.17 +/- .96 hours (n = 18) compared with 14.7 +/- 6.3 hours for fTcSC (n = 6). The mean sentinel lymph node uptakes of Lymphoseek (.73% +/- .94%) and fTcSC (.85% +/- 1.19%) were statistically equivalent (P = .68). Lymphoseek exhibited a lower mean number of sentinel lymph nodes per basin (1.6) than fTcSC (1.9). No adverse events were observed, nor were any clinically significant alterations in laboratory parameters. Radiation absorbed doses were lower than filtered [(99m)Tc]sulfur colloid. CONCLUSIONS: The molecular imaging agent Lymphoseek demonstrated faster injection site clearance and equivalent primary sentinel node uptake when compared with filtered [(99m)Tc]sulfur colloid.

Adult↗

Molecular targeting of the lymphovascular system for imaging and therapy.

Progress toward targeting cancer cells is a multi-disciplinary endeavor. In addition to the surgical and oncology specialties, radiologists collaborate with mathematicians, computer scientists, and physicists, in a constant effort to incrementally improve upon the current imaging modalities. Recently, radiologists have formed collaborations with molecular biologists and chemists in order to develop molecular agents that target cancer cells via receptor-substrate or specific physiochemical interactions. In this review, we summarize selected efforts toward molecular targeting of the lymphovascular system. Standard imaging modalities, positron emission tomography, single photon emission tomography, and ultrasound, are reviewed as well as, the targeted introduction of substances for endolymphatic therapy. We also review the current status of sentinel lymph node mapping with radiocolloids and the application of molecular targeting for the development of a radiopharmaceutical specifically designed for sentinel lymph node mapping.

Animals↗

Minimally invasive sentinel lymph node mapping of the pig colon with Lymphoseek.

BACKGROUND: Minimally invasive surgery and sentinel node mapping are being utilized increasingly in colon cancer surgery. Making these techniques efficient and easy to perform will be essential for the future of this and other gastrointestinal operations. The purpose of this study was to test a new laparoscopic gamma detection probe for minimally invasive sentinel node mapping of the colon, while utilizing Lymphoseek, a radiopharmaceutical specifically designed for sentinel lymph node (SLN) detection. METHODS: Eight anesthetized pigs received an endoscopic co-injection of Lymphoseek and Isosulfan Blue in the colon. The laparoscopic gamma detector, inserted via a 12-mm trocar, was used to identify radioactive sentinel lymph nodes. The reliability of the side-viewing probe was tested using a radioactive source. All blue and radioactive lymph nodes were excised and the signal-to-background ratio (S/B) and percent of injected dose (%ID) were measured. RESULTS: The probe was easy to maneuver and led to efficient visualization of the radioactive node. The side port allowed for better distinction between injection site scatter and sentinel node activity. The reliability of the probe was validated by an identification rate of 97%. At least one SLN was detected for each pig; two SLNs were detected in two pigs. All SLNs were stained blue. The SLN S/B ranged from 38 to 315 and the %ID ranged from 0.06% to 2.01%. Sentinel nodes were found within 10 minutes. CONCLUSIONS: Minimally invasive sentinel node mapping with the radiopharmaceutical Lymphoseek and a side-viewing gamma detector yielded high S/B and directionality for accurate mapping of gastrointestinal sentinel lymph nodes within minutes of radiotracer administration.

Animals↗

A preclinical study of prostate sentinel lymph node mapping with [99mTC]diethylenetetramine pentaacetic acid-mannosyl-dextran.

PURPOSE: SLN identification could improve the pathological staging of prostate cancer. Prior SLN studies have been compromised by delayed radiotracer uptake rates and significant diffusion rates out of the sentinel nodes. Lymphoseek is a new radiopharmaceutical specifically designed for SLN mapping. It shows rapid and sustained SLN uptake. MATERIALS AND METHODS: We investigated the use of Lymphoseek for prostate SLN mapping by measuring SLN uptake in 12 anesthetized pigs. The prostate was injected with 0.05 ml of a 1:1 volume per volume mixture of Lymphazurin and 1.0 mCi Lymphoseek (1 nmole). Within 5 to 19 minutes the pelvic lymph nodes were dissected and assayed with a gamma probe. A lymph node was considered a sentinel node if it had count rates that exceeded 10 times the background count. We calculated the percent of injected dose of each lymph node excised and the prostate gland. RESULTS: A total of 35 SLNs were identified in the 12 studies. Of the SLNs 81% were located outside of the obturator fossa in this pig model. The SLN percent of injected dose was 0.05% to 7.75% (mean +/- 1 SD 1.74% +/- 1.92%). The mean percent of injected dose in the prostate was 27% +/- 12%. There was no correlation between the side of SLN and the lobe injected. CONCLUSIONS: After prostate administration of Lymphoseek pelvic SLNs attain high signal-to-background ratios within 10 minutes. This property should permit intraoperative injection and SLN mapping without significantly adding to the duration of prostatectomy. A phase I clinical trial has been initiated, which will later incorporate minimally invasive techniques.

Animals↗

Cy5.5-DTPA-galactosyl-dextran: a fluorescent probe for in vivo measurement of receptor biochemistry.

The high sensitivity of fluorescent reporters offers an opportunity to analytically probe the biochemistry of in vivo receptor systems with low target tissue concentration. We investigated the ability of an optical imaging system to acquire adequate signal for in vivo measurement of receptor biochemistry. The imaging system consisted of a small animal optical imager operating in the time domain (TD) and a fluorescent-labeled diagnostic probe of known receptor-binding properties. Optical imaging of mice (n = 4) using the targeted probe, Cy5.5-DTPA-galactosyl-dextran (2.2 Cy5.5, 4 DTPA, 68 galactose units per dextran, 124 kDa, 24 nmol/kg), demonstrated blood clearance and hepatic uptake. The mean and standard deviation for the time to reach 90% of the peak liver intensity were 15.4 +/- 1.6 min. Typical fluorescent intensities within a 10-pixel region-of-interest from a 30-s image acquired 30 min postinjection were in excess of 2.5 million counts. The nontargeted agent (Cy5.5-DTPA-dextran) did not demonstrate (n = 4) hepatic uptake. This uptake pattern was duplicated by nuclear imaging of rabbits using (99m)Tc-labeled Cy5.5-DTPA-galactosyl-dextran and Cy5.5-DTPA-dextran. This study demonstrated the feasibility of optically labeling a receptor-binding diagnostic probe and imaging in the TD with sufficient sensitivity and temporal resolution for pharmacokinetic analysis.

Animals↗

What is to be gained by imaging the same animal before and after treatment?

Experimental design includes decisions to perform measurements with intact animals or truncated in vivo measurements followed by dissection and ex vivo measurements. The design may be driven by advantages and disadvantages of the choices. Analytical results are presented here that can provide a basis for certain experimental design choices. Design considerations include longitudinal studies in the single animal that bracket a treatment, joint observations by supplementing the imaging data with plasma and/or ex vivo sampling after dissection, multiple injections of increasing molar base or administration of a molar dose that results in the occupation of a significant fraction of the target receptors. Of particular interest when constructing an experimental design is the reduction of bias. Analysis tools for this purpose include reparameterization and model application without the formation of time-based averaging.

Animals↗

Are there lessons to be learned from drug development that will accelerate the use of molecular imaging probes in the clinic?

This special issue of the journal contains contributions from participants of the third La Jolla meeting (The Magic Bullet: A Century Later). The goal of this meeting was twofold: to review approaches to validating molecular imaging agents and to review the progress in advancing the use of molecular imaging from the bench to the bedside, with a special emphasis on how molecular imaging improves patient care and management. Drug development has changed its focus over the years. The original approach depended on direct measurements in patients, whereby, in many cases, the drug was advanced to an NDA based on physiological results (e.g., lowering blood pressure) without identifying a target. Over the past decade, the focus has been on validating a target and choosing the lead compound using combinatorial chemistry and high throughput screening, often at the expense of a focus on the biology of diseases. On the other hand, molecular imaging has been target based since its beginning because of the requirements dictated by external imaging (i.e., a target-to-nontarget ratio). This article explores the possible analogies between current targeted drug development and molecular imaging-targeted probe development with the goal of better defining the path to new molecular imaging probes for the clinic.

Animals↗

Breast imaging: a surgeon's prospective.

Mammography, ultrasound, magnetic resonance imaging, positron emission tomography, gamma camera and intraoperative gamma detection, and computed tomography are employed in the diagnosis and treatment of breast cancer. This paper summarizes the role of each modality from the perspective of the physician responsible for management of the patient's care. An understanding of an imaging modality's current role can provide insights into the design of new applications and diagnostic agents. Moreover, knowledge of the mechanism by which each modality provides clinical information can guide the design of new imaging methods that complement and add certainty to the patient's management. The reader should note the lack of molecular information provided by the current imaging methods. The perspective concludes with a request for an imaging technique that can measure the biologic aggressiveness of a woman's cancer. The surgeon notes that basing the formation of an image on a molecular process would be compatible with current medical practice, which utilizes molecular concepts to base medical decisions. In addition, molecular imaging will enable rapid translation between basic science and medical practice.

Breast Neoplasms↗

Gadolinium-DTPA-dextran: a macromolecular MR blood pool contrast agent.

RATIONALE AND OBJECTIVES: Magnetic resonance (MR) imaging blood pool agents offer numerous advantages for vascular and tumor imaging. The purpose of this study was to test gadolinium-diethylenetriaminepentaacetate-dextran ([Gd]DTPA-dextran) as a new water soluble macromolecular blood pool agent for MR imaging. MATERIALS AND METHODS: [Gd]DTPA-dextran (187 gadolinium atoms per dextran, molecular weight 165 kD, diameter 17.6 nm) was synthesized. Fifteen anesthetized New Zealand White rabbits with thigh VX2 tumors were scanned in a knee coil at 1.5T. Coronal 3D MR angiographic sequences were obtained before and at several time points up to 72 hours after the intravenous bolus injection of [Gd]DTPA-dextran providing gadolinium at either 0.05 (n = 4) or 0.1 mmol/kg (n = 8) or [Gd]DTPA-bismethylamide (BMA) providing gadolinium at 0.1 mmol/kg (n = 3). Time enhancement curves for aorta, cava, and tumor rim were compared by univariate General Linear Model. RESULTS: Contrast enhancement of cava and aorta relative to a water phantom were significantly greater at all time points after either dose of [Gd]DTPA-dextran than after [Gd]DTPA-BMA (P < 0.01). Tumor rim enhancement was less intense for either dose of [Gd]DTPA-dextran at peak than for [Gd]DTPA-BMA (P < 0.05). Tumor rim enhancement with both doses of [Gd]DTPA-dextran became equivalent to that of [Gd]DTPA-BMA at one hour and was greater at 24 hours (P < 0.05). CONCLUSION: [Gd]DTPA-dextran is a new macromolecular MR contrast agent that can be synthesized to carry a high density of gadolinium atoms without intra-molecular cross-linking. It provides significantly greater vascular residence time than a conventional gadolinium chelate and shows promise for MR blood pool imaging.

Animals↗

Sentinel lymph node mapping of the colon and stomach using lymphoseek in a pig model.

BACKGROUND: Lymphoseek is a radiopharmaceutical designed for sentinel lymph node (SLN) mapping. The purpose of this study was to compare Lymphoseek colon and gastric pharmacokinetics with filtered [(99m)Tc]sulfur colloid (fTcSC). METHODS: Eight anesthetized pigs received an endoscopic injection of Lymphoseek or fTcSC in the stomach and colon. Scintigraphy was obtained of both administration sites at 15-minute intervals up to 3 hours after injection, after which all SLNs were identified by a handheld gamma probe through a laparotomy incision. Isosulfan blue was administered at the injection site 5 minutes before SLN mapping. The percentage of injected dose (%ID) was measured for all harvested nodes, and the clearance half-life (T(c)) was calculated for all injection sites. RESULTS: The mean Lymphoseek clearance for colon (T(c), 2.56 +/- 1.04 hours) and gastric (T(c), 3.83 +/- 1.18 hours) injection sites was statistically faster (P =.030) compared with fTcSC (colon T(c), 14.98 +/- 3.41 hours; stomach T(c), 14.52 +/- 4.08 hours). After 3 hours, Lymphoseek exhibited a mean SLN %ID of 1.32% +/- 1.71% in the colon and 2.04% +/- 2.12% in the stomach; this was not statistically different from fTcSC (colon,.63% +/-.39%; stomach, 2.35% +/- 2.90%). SLN uptake of Lymphoseek was significantly different from second-echelon node %ID for the colon (P =.011) and gastric (P =.029) injection sites. All SLNs exceeded 10 times background, and there was no discordance between isosulfan blue and Lymphoseek or fTcSC. CONCLUSIONS: Three hours after colon stomach administration, Lymphoseek demonstrated rapid injection site clearance, detectable SLN uptake, and low second-echelon node uptake.

Animals↗

Dose-dependent biodistribution of [(99m)Tc]DTPA-mannosyl-dextran for breast cancer sentinel lymph node mapping.

[(99m)Tc]DTPA-mannosyl-dextran is a receptor-binding radiopharmaceutical specifically designed for sentinel lymph node mapping. The purpose of this study was to test the biodistribution and safety of [(99m)Tc]DTPA-mannosyl-Dextran at different molar doses. Twenty-four female breast cancer patients participated in this study. Four groups of 6 patients received an injection of 0.2, 1.0, or 5.0 nmol of [(99m)Tc]DTPA-mannosyl-Dextran or filtered [(99m)Tc]sulfur colloid. The injection site clearance was monitored by dynamic imaging for three hours. Whole body scans were acquired at 2.5 and 12, and lymph nodes were assayed for radioactivity after gamma-guided sentinel lymph node biopsy. Injection site clearance of [(99m)Tc]DTPA-mannosyl-Dextran was not statistically different in a dose-dependent manner. Dose-dependent sentinel node uptake was observed (p = 0.03). There were no clinically significant alterations in laboratory parameters among all dose levels at 4 h or 24 h post injection compared to preoperative levels. Radiation absorbed doses did not differ among the three dose levels, but were lower than filtered [(99m)Tc]sulfur colloid.

Adult↗

Preclinical studies of [(99m)Tc]DTPA-mannosyl-dextran .

We report the preclinical testing of a synthetic receptor-binding macromolecule, [(99m)Tc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, K(D) = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration, and perivascular irritation studies in rabbits following intra-muscular administration at 100 and 1000 times the scaled human dose. Biodistribution studies in rabbits at 15 m, 1 h, and 3 h indicated that [(99m)Tc]DTPA-mannosyl-dextran cleared the hind foot pad with a biological half-life of 2.21 +/- 0.27 h. Other than mild hepatocyte hypertrophy in rabbits, no abnormalities in toxicology or pathology were found. Intravenous administration had no effect on survival, any clinical observations, electrocardiograms, or blood pressures. Intramuscular injection had no effect on survival, clinical observations, injection site observations, or injection site histopathology. The estimated absorbed radiation dose to the affected breast was 0.15 mGy/MBq and the effective dose was 1.06 x 10(-2) mSv/MBq. This preclinical study demonstrates that [(99m)Tc]DTPA-mannosyl-dextran has no toxicities and has an acceptable biodistribution and radiation dose.

Animals↗

Clinical application of TcGSA.

Asialoglycoprotein receptor (ASGP-R) is a hepatic cell surface receptor specific for galactose-terminated glycoprotein. The (99m)Tc-labeled asialoglycoprotein analog, TcGSA (galactosyl-human serum albumin-diethylenetriamine-pentaacetic acid) has been applied to human hepatic receptor imaging. This method is unique and provides information that is totally independent of the ICG test or Child-Turcotte Score. However, simple parameters, HH15 or LHL15 are no better than conventional Child-Turcotte Score. Parameters obtained from kinetic modeling were useful in detecting liver cirrhosis or postoperative liver failure. They provide quantitative data on functioning liver mass. Considering the moderate cost and widespread availability of gamma cameras, a TcGSA test should be performed on patients whose liver function are not adequately estimated by an ICG test or a Child-Turcotte score.

Animals↗

Lymphoseek: a molecular radiopharmaceutical for sentinel node detection.

BACKGROUND: Lymphoseek is a new radiopharmaceutical that accumulates in lymphatic tissue by binding to a receptor that resides on the surface of macrophage cells. We conducted a phase I clinical trial in which Lymphoseek was compared with filtered [(99m)Tc]sulfur colloid (fTcSC) for sentinel node detection in patients with breast cancer. METHODS: Twelve women (42-71 years) with breast cancer were randomly assigned to a 3-hour imaging protocol with peritumoral/subdermal injections (.5 mCi) of either Lymphoseek (1 nmol; molecular weight, 28 kDa; diameter,.007 micro m) or.2 micro m of fTcSC. Serial images were acquired for 180 minutes. Sentinel nodes, excised within 4.2 to 7.3 hours of administration, were assayed in a dose calibrator. RESULTS: The receptor-binding agent, Lymphoseek, exhibited a significantly (P =.0025) faster injection site clearance (rate,.255 +/-.147/hour; fTcSC rate,.014 +/-.018/hour); the mean Lymphoseek clearance half-time was 2.72 +/- 1.57 hours compared with 49.5 +/- 38.5 hours for fTcSC. The primary sentinel node uptake of Lymphoseek (range,.02%-1.12%; mean,.55% +/-.43%) and fTcSC (range,.00%-1.93%; mean,.65% +/-.63%) did not differ (P =.75). Lymphoseek exhibited a lower mean number of sentinel nodes per study (n = 1.3) than fTcSC (n = 1.7) and a higher concordance with Lymphazurin. CONCLUSIONS: The molecular receptor-binding agent Lymphoseek demonstrated faster injection site clearance and equivalent primary sentinel node uptake when compared with fTcSC.

Adult↗

Detection of gastric and colonic sentinel nodes through endoscopic administration of 99mTc-DTPA-mannosyl-dextran in pigs.

UNLABELLED: The purpose of this study was to develop a method for the endoscopic administration of a radiopharmaceutical for sentinel node detection and to characterize its uptake by gastric and colonic sentinel nodes. (99m)Tc-Diethylenetriaminepentaacetic acid (DTPA)-mannosyl-dextran is a new radiotracer labeled with (99m)Tc and composed of multiple units of mannose attached to the polymeric backbone, dextran. METHODS: Gastric and colonic lymph node detection was studied in 4 fasting and anesthetized pigs. A flexible video endoscope was inserted into the rectum and positioned in the lower colon or advanced down the esophagus into the stomach. A standard endoscopic sclerotherapy needle and sheath filled with 0.9% saline was then loaded with 0.2 mL of a 7.4-MBq 1:1 (v/v) mixture of isosulfan blue and (99m)Tc-DTPA-mannosyl-dextran (7.4 MBq, 0.3 nmol). The needle and sheath were passed through the biopsy channel, and the radiotracer/dye solution (0.1 mL) was injected in a tangential fashion into the submucosa. Within 5-10 min after injection, all radioactive or blue lymph nodes were excised, assayed for radioactivity, and noted for color. Distal lymph nodes were also excised, assayed, and noted for color. RESULTS: (99m)Tc-DTPA-mannosyl-dextran uptake by colonic sentinel nodes (n = 4) ranged from 0.54% to 2.4% of the injected dose; all radioactive nodes were stained blue. The uptake for all (n = 3) distal nodes ranged from 0.001% to 0.005%, and none of these nodes were stained blue. Uptake by gastric sentinel nodes (n = 6) ranged from 0.13% to 4.50%; all radioactive nodes were stained blue. The range for distal nodes was 0.001% to 0.050%; no distal nodes were stained blue. In 2 pigs, each gastric injection produced 2 hot and blue lymph nodes. CONCLUSION: Within 10 min of a gastric and colonic submucosal injection, (99m)Tc-DTPA-mannosyl-dextran demonstrated high sentinel node uptake and high concordance with isosulfan blue.

Animals↗

Predictors of successful hepatic resection: prognostic usefulness of hepatic asialoglycoprotein receptor analysis.

To test the clinical usefulness of hepatic asialogycoprotein receptor analysis in liver surgery, we have conducted univariate and multivariate analysis for the detection of cirrhotic patients and prediction of morbidity after hepatic resection. Liver scintigraphy using technetium 99m-labeled asialoglycoprotein analog (TcGSA), ICG test, and CT hepatic volumetry were undertaken in 158 surgical patients including 111 who underwent hepatic resection. Hepatic functional parameters including Child-Pugh score, indocyanine green retention at 15 minutes (ICG-R15), clearance index (HH15), receptor index (LHL15), receptor concentration ([R]0), total hepatic receptor amount (R0) and hepatic parenchymal volume (HPV) were compared among patients with normal, cirrhotic, and non-cirrhotic damaged liver. Preoperative hepatic functional parameters, resected parenchymal fraction (RPf), operative blood loss, and total receptor amount of the remnant liver (R0-remnant) were compared between patients with and without signs of postoperative liver failure. All parameters but HPV were significantly different among patients with normal, cirrhotic, and noncirrhotic damaged liver. The multivariate analysis selected two significant (p <0.05) parameters, [R]0 and Child-Pugh score for the detection of liver cirrhosis. Of the 111 patients who underwent resection, 14 developed transient signs of postoperative liver failure. Of the parameters tested, presence of liver cirrhosis, LHL15, R0, intraoperative blood loss, and R0-remnant were significantly different between patients with and without signs of postoperative liver failure (p <0.05). The multivariate logistic regression analysis selected only R0-remnant as a significant (p = 0.022) parameter for the prediction of liver failure. The morbidity rate in patients with R0-remnant under 0.05 mmoles was 100%, and the rate decreased in inverse proportion to R0-remnant. In conclusion, combining the ASGP-R concentration ([R]0) and the Child-Pugh score best detected liver cirrhosis in surgical candidates. Cirrhotic patients and patients with a low R0-remnant are at higher risk for postoperative liver failure. The present study confirms the usefulness of hepatic asialogycoprotein receptor analysis in liver surgery.

Adult↗